tbuckley/cabot-search huggingface dataset:
Three-year outcomes and correlative analyses in patients with non–small cell lung cancer (NSCLC) and a very high PD-L1 tumor proportion score (TPS) ≥ 90% treated with first-line pembrolizumab.
Authors: Biagio Ricciuti, Arielle Elkrief, Joao Victor Machado Alessi, Xinan Wang, Adriana Paula de Castro Barrichello, Federica Pecci, Giuseppe Lamberti, James Lindsay, Bijaya Sharma, Kristen Felt, Mizuki Nishino, Lynette M. Sholl, Scott J. Rodig, Adam Jacob Schoenfeld, Mark M. Awad
Journal: Journal of Clinical Oncology (2022)

9043 Background: Although 1 st -line PD-1 monotherapy has improved survival in advanced NSCLC with a PD-L1 TPS ≥50%, responses occur in ̃45% of patients (pts). We previously showed that among pts treated with 1 st -line pembrolizumab, clinical outcomes were significantly improved in those with a PD-L1 TPS of ≥90% compared to a TPS of 50-89%. Here, we report the 3-year survival analysis to 1 st -line pembrolizumab in pts with a PD-L1 TPS ≥90% vs 50-89%, and characterize genomic and immunophenotypic differences between these PD-L1 expression groups. Methods: Pts with stage IV EGFR/ALK wild-type NSCLC and PD-L1 TPS ≥50% who received 1 st -line pembrolizumab at the Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering Cancer Center (MSKCC), with a minimum follow-up of 3 years were included. Comprehensive tumor genomic profiling and multiplexed immunofluorescence (mIF) were performed to examine genomic and immunophenotypic correlates of very high PD-L1 expression on separate cohorts of NSCLC at the DFCI. Results: Among 396 pts, median age was 69, 53.3% were women, 90.1% had a history of tobacco use, 83.6% had a ECOG performance status of 0-1, and 28.8% had a KRAS mutation. At a median follow-up of 42.6 months, median progression-free (mPFS) and overall survival (mOS) in the entire cohort were 5.1 months, and 19.0 months, respectively. When compared to pts with a PD-L1 TPS of 50-89% (N = 252), those with PD-L1 TPS ≥90% (N = 144) had a significantly longer mPFS (6.0 vs 4.5 months, HR 0.67, p &lt; 0.001), and longer mOS (30.2 vs 16.9 months, HR 0.66, p &lt; 0.01). Kaplan-Meier estimates of the 3-year PFS and OS were 24.9% and 47.0% in the PD-L1 TPS ≥90% groups, and 9.4% and 27.7% in the PD-L1 TPS 50-89% group, respectively. A PD-L1 TPS ≥90% was confirmed to be an independent predictor of improved PFS (HR 0.68, p &lt; 0.01) and OS (HR 0.67, p &lt; 0.01) in multivariable analysis. Tumor genomic profiling from a separate cohort of 500 NSCLC samples revealed that mutations in STK11, KEAP1, FBXW7, and CTNNB1 were significantly more frequent in tumors with a PD-L1 TPS of 50-89% compared to those with a PD-L1 TPS ≥90% (q &lt; 0.05). mIF on 91 NSCLCs identified significantly higher CD8+PD1+ T cells and PD-L1+ immune cells in tumors with PD-L1 TPS ≥90% vs 50-89% (p &lt; 0.05). Conclusions: Pembrolizumab monotherapy continues to demonstrate a meaningful long-term survival benefit in pts with advanced NSCLC and a PD-L1 TPS ≥90%. NSCLCs with very high PD-L1 TPS may have a more favorable genomic and immunophenotypic profile. These findings have implications for treatment selection and clinical trial interpretation and design.
Blood monocyte and lymphocyte counts patient outcomes in non-small cell lung cancer after immune checkpoint inhibitor therapy: Real-world data of 12,416 patients.
Authors: Jerome H. Goldschmidt, Philip K Chan, Lin-Na Chou, Liwei Chen, Nicholas J. Robert, Joyce Kinsey, Matt Nestor, Hillard M. Lazarus, Edwin P. Rock
Journal: Journal of Clinical Oncology (2022)

e21023 Background: Immune checkpoint inhibitors (ICPi) are now commonly used in non-small cell lung cancer (NSCLC) treatment. Beyond PD-L1 status, no clinically validated predictive biomarkers guide therapeutic decision making regarding their use. Blood monocyte, lymphocyte counts, or their ratio might inform clinical utility of these expensive, potentially toxic agents. Methods: Adults with advanced/metastatic NSCLC receiving any ICPi after diagnosis from January 2015 to November 2020 were included. Treatment outcomes were followed until 31 May 2021. Data were sourced from structured fields of electronic health records from The US Oncology Network and non-Network practices. The primary end point was overall survival (OS), and time to treatment discontinuation (TTD) was secondary. Baseline absolute monocyte count (AMC), absolute lymphocyte count (ALC), and monocyte-to-lymphocyte ratio (MLR) were subdivided into quintiles (Q) with Q1 lowest and Q5 highest. Patient (pt) and treatment characteristics were described. Time-to-event outcomes were assessed by Kaplan-Meier methods. Univariate and multivariate Cox regression analyses described associations among baseline biomarkers, OS, and TTD. Results: For 12,416 pts with NSCLC, median OS and TTD were 13.6 months (mos) and 4.5 mos, respectively. For AMC, patients in Q2 and Q3 had the longest median OS of 15.9 mos. Median TTD by AMC was longest for Q1 and Q2 (5.1 mos), declining sequentially to 3.3 mos for Q5. For ALC, Q5 had longest median OS of 19.2 mos, as well as longest median TTD of 5.8 mos. For MLR, Q1 had the longest median OS and TTD of 22.3 and 6.2 mos., respectively. In univariate Cox regression, AMC, ALC, and MLR each associated with OS and TTD (p &lt; 0.0001). Pts in AMC Q5, compared with AMC Q1, had an OS hazard ratio (HR) of 1.48 (95% CI 1.38-1.60). For ALC, each successive increasing quintile, compared to ALC Q1, demonstrated a lower risk of death (p &lt; 0.0001). Pts in MLR Q5, compared with MLR Q1, had an OS HR of 2.21 (95% CI 2.04-2.39). Conclusions: This data set is the largest to date to examine interactions among baseline immune cell counts, ICPi use, and pt outcome in NSCLC. These data inform efforts to describe immune-based prognostic risk groups among NSCLC pts receiving immunotherapy.[Table: see text]
Does targeted temperature management increase the risk of stent thrombosis in survivors of out-of-hospital cardiac arrest? A single centre experience
Authors: R Kanji, YX Gue, AM Saw, MQ Shahid, DA Gorog
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Acute Myocardial Infarction (AMI) complicated by out-of-hospital cardiac arrest (OCHA) carries a poor prognosis. Emergent angiography and primary percutaneous coronary intervention (PPCI) has been shown to improve survival, however some patients are left with significant neurological sequelae. Targeted Temperature Management (TTM) in randomised controlled trials has improved neurological status in survivors, however concerns have arisen from case series demonstrating a higher incidence of stent thrombosis. Reduced absorption of orally-administered P2Y12 inhibitor medication has been demonstrated in this cohort on the intensive care unit (ICU) and has been proposed to account for an observed increase in stent thrombosis. Purpose Our aim was to assess the relationship between stent thrombosis and TTM in patients with OHCA due to AMI and undergoing primary percutaneous coronary intervention (PPCI). Methods We conducted a single centre, retrospective analysis of consecutive patients admitted to the East and North Hertfordshire NHS Trust with an OHCA secondary to ST-elevation myocardial infarction and treated with PPCI. All patients received aspirin loading and either enteral P2Y12 inhibitor loading (ticagrelor or clopidogrel) or intravenous (cangrelor) prior to or immediately after PPCI, according to clinician preference. Glycoprotein IIb/IIIa administration was determined by physician choice and documented. All patients were transferred to the ICU straight after PPCI, where some received TTM. Notes were reviewed to allow recording of demographic and procedural data, including post resuscitation care up to hospital discharge. Results A total of 92 patients were identified, 80% male and aged 62 +/-12.5 years. In addition to aspirin, patients were treated with P2Y12 inhibitors with 72.5% loaded with ticagrelor, 2.5% with clopidogrel and the remaining 25% with intravenous cangrelor. In addition, 49% of patients received periprocedural glycoprotein IIb/IIIa inhibitor. TTM was initiated in 38 patients (41%) using surface pads. The average duration of TTM was 24 hours. No cases of stent thrombosis occurred. In-hospital all-cause mortality was 24%. The death rate was higher amongst those patients who were cooled, but this difference was not statistically significant (35% vs 17%, p = 0.08). Cangrelor use was significantly higher in the cooled cohort (43% vs. 8%, p &amp;lt; 0.001), but glycoprotein IIb/IIIa inhibitor use was similar between those receiving and not receiving TTM (38% vs. 57%, p = 0.088). Conclusion No definite stent thromboses were recorded in the 92 patients reviewed, suggesting that TTM does not increase the risk of stent thrombosis. Our conclusion is limited by the small sample size, and the heterogeneity in P2Y12 inhibitor use, particularly the higher use of cangrelor in the cooled cohort.
Validity of mutations as a cancer chronometer.
Authors: Farhan Kawsar, Ahmad Mazen Safar, Jim Zhongning Chen
Journal: Journal of Clinical Oncology (2022)

e15015 Background: Staging is devised to assess prognosis, and ultimately direct the management of cancer. Though staging systems don't necessarily confirm chronological progression from stage I to IV, there is near consensus that advanced stages are 'later' versions of a given cancer. This is reflected in the philosophy and efforts to identify 'early' cancer in screening programs. Tumor Mutational Burden (TMB) is one measure of the degree of proliferation, thus can be utilized as a molecular clock (Vogelstein), a surrogate for chronology. Since TMB is currently a clinical metric provided to oncologists in routine practice, proper interpretation of TMB is critical. We hypothesized that (i) metastatic disease is a ‘different’, rather than 'later' manifestation of a given cancer. Furthermore, we hypothesized that (ii) proliferation rates would be mirrored by the TMB, and lastly, that (iii) TMB will correlate with clinical virulence. Methods: (i) We mined the publicly-available TCGA database (cbioportal.org) for TMB from 558 samples spanning 5 whole genome &amp; whole exome neoplasm datasets (Breast, Colon, Renal cell, Pancreatic, Cervical cancers). (ii) We compared the TMB in Burkitt's lymphoma, a highly proliferative neoplasm, with follicular lymphoma, a classically quiescent malignancy. (iii) We compared the TMB in skin squamous cell carcinoma (SSCC), a cancer with negligible impact on survival, with Acute Myelogenous Leukemia (AML), a highly lethal malignancy despite aggressive therapy. Results: (i) The 95% Confidence Intervals (CI) surrounding the median TMB were overlapping without statistical significance across ALL stages within EVERY histology examined. (ii) To our surprise, the TMB 95% CI were overlapping between the 2 subsets of B-cell lymphoma examined. (iii) TMB was substantially higher in SSCC (median of ̃800) compared to a mere 8 in AML. Conclusions: Assuming validity of Vogelstein’s molecular clock model, mutational probing does not support the concept that a stage IV malignancy is a chronologically delayed manifestation of a given neoplasm. Rather, we suggest an alternative approach where aggressive/metastatic cancers are inherently 'different' with unique abilities rather than a ‘later’ edition of a monodirectional succession. We also posit that cells that live for years (follicular lymphoma) can accumulate comparable levels of TMB as Burkitt's because the limited life span in Burkitt's (days to weeks) precludes the accumulation of high TMB. Finally, the clinical outcome cannot be discerned from the degree or mutability— which is rationally a predictor of immune susceptibility. It's noteworthy that the observed levels of mutations in SSCC, reflective of the sun mutagenicity, is more than 3-fold of that reported for melanoma (̃274) but this fact is rarely presented in cancer genomic landscapes, and may explain the rarity of metastatic SSCC owing to the immune clearance of metastases unlike the skin surface devoid of such immune access.
The use of patient experience in improving the care pathway for patients with head and neck cancer undergoing radio-chemotherapy.
Authors: Camelia Billard, Anne De Jesus, Gabriela Dumitrescu, Michel Cremadez, Bernard Escudier, Eric Deutsch
Journal: Journal of Clinical Oncology (2022)

e18625 Background: Patient satisfaction with the care received or the judgment that patients make of the quality of their care, is now recognized as essential in assessing the quality of health care. Patients and the caregivers have additional experiential knowledge that hospitals must consider in order to improve theirs performance. Methods: The objectives of our study was to determine the key points to be improved in the complex multidisciplinary course of the patient with advanced head and neck cancer undergoing curative treatment by radio-chemotherapy at Gustave Roussy oncological centre in France. To do this, we considered that the collection of the experience of patients, who had recently finished or were still in the process, was essential to design a patient course that takes into account their legitimate expectations. We realised a qualitative research in the form of an interview survey. Seven patients who completed their treatments at different times from October 2020 to September 2021 and four patients still undergoing radio chemotherapy between October to December 2021 gave their consent and participated in the study. We conducted eight face-to-face interviews, one by telephone and two by teleconference between September 2021 and January 2022. All interviews were conducted with two interviewers. Having opted for non-directive interviews, we have limited our interventions as much as possible, depending on the rhythm and content of each patient's story. Our questions focused on points the patient had not addressed by himself. Results: Patients consider the circuits of care to be fluid and the staff to be very attentive. They feel confident, respected and receive personalized care before and during the radio-chemotherapy. Nevertheless, most of the patients mentioned the lack of coordination between the carers of different specialties (medical oncology, radiotherapy, head and neck surgery) and between the institute and the home carers with difficulties in managing toxicities, especially post-treatment. Another breaking point has been the lack of information offered by medical staff about supportive care and cancer patient associations. Conclusions: Several areas for improvement emerged with regard to the coordination of care during treatment and the monitoring of post-treatment side effects. Therapeutic education, prevention and management of toxicities by specialized nurses may respond to this problem as well as digital applications in oncology. A complementary solution can be the implementation of peer patients for this complex head and neck cancer patients course. Our work will continue with a quality research on the impact of nurse-peer patient partnership.
Regional block pilot for microvascular free-flap breast reconstruction.
Authors: Leah Kim, Anne Long, Jared Miller, Holly Zurich, Mehra Golshan, Jinlei Li
Journal: Journal of Clinical Oncology (2022)

e18646 Background: With increasing focus on improving patient outcomes and decreasing narcotic use, healthcare has prioritized the use of multidisciplinary, multimodal, and evidence-based approaches to perioperative management through enhanced recovery after surgery (ERAS) pathways. Currently, microsurgical breast reconstruction with or without concurrent mastectomy commonly may employ regional anesthesia in the preoperative and intraoperative techniques. To optimize perioperative analgesia, an ERAS protocol was piloted at a quaternary care academic center implementing a pre-operative anesthesia placed regional block with preference for anterior quadratum lumborum blocks. Methods: A total of 161 patients were enrolled in this single center Continuous Quality Improvement (CQI) project. The project consisted of 72 baseline, 20 pilot, and 69 after pilot patients who underwent unilateral (n = 65) or bilateral (n = 96) deep inferior epigastric perforator (DIEP) flap reconstruction either immediately (n = 87) or delayed (n = 74) after mastectomy. In the 20 CQI pilot group, anesthesiologists pre-operatively placed bilateral anterior quadratus lumborum blocks (aQLB) under direct ultrasound guidance. After positively observed metrics, the official ERAS pathway was implemented into clinical practice, allowing for subsequent accrual of 69 additional patients. We compared this after pilot group to 72 baseline patients who underwent a surgeon-placed intraoperative transversus abdominus plane (TAP) block using liposomal bupivacaine. Statistics data was tracked using a dedicated clinical EMR dashboard. Baseline patients were matched to the after pilot cohort based on laterality and timing of DIEP flap reconstruction. Results: The ERAS pathway with anesthesia-placed aQLB was associated with lower post-operative daily opioid consumption from 27.2 MME to 10.2 MME. Average pain scores, post-anesthesia care unit (PACU) length of stay, hospital length of stay, as well as re-admissions and complications were not statistically different before and after the implementation of the ERAS pathway. Conclusions: Anesthesia placed pre-operative aQLB is a safe and effective opioid-reducing pain control modality for DIEP flap reconstruction with or without mastectomy. Prospective and controlled studies will be important for the precise impacts of aQLB in DIEP procedures in an ERAS protocol.[Table: see text]
MEDB-58. Risk factors and risk prediction models for medulloblastoma recurrence
Authors: Juan Li, Mingyao Lai, Linbo Cai
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: There is a clear need for systematic appraisal of models/factors predicting medulloblastoma recurrence because clinical decisions about adjuvant treatment are taken on the basis of such variables. METHODS： A total of 273 patients diagnosed with medulloblastoma were retrospectively analyzed. The pre-rediotherapy neutrophile-lymphocyte ratio (NLR) was calculated, and other clinical characteristics were collected such as genetic type , whether with dissemination, degree with excision. The Kaplan-Meier method was used for survival analysis. Cox regression models was used to identify independent prognostic factors. R software was used to develop a nomogram with all the independent prognostic factors included. The prognostic predictive ability of the nomogram was evaluated by Concordance-index (C-index), area under the curve (AUC), and calibration curve. RESULTS: The median median progression-free survival time was 63.8 months in overall cohort. Univariate and multivariate cox hazards regression analysis identified independent prognostic factors associated with the PFS of patients with medulloblastoma to include age, residual tumor volume ＞1.5cm3 after excision, NLR ＞4.5, whether with dissemination before RT, and whether the genetic type is group 3,which were integrated to establish a nomogram. The C-indexes of nomogram were 0.696 and 0.676 in the training and validation cohort, respectively. The AUC of predicting 3-years PFS showed satisfactory accuracy as well (Training cohort: AUC=0.696; Validation cohort: AUC=0.676). The calibration curve showed agreement between the ideal and predicted values. Kaplan-Meier curves based on the PFS showed significant differences between nomogram predictive low-, and high groups (P &amp;lt; 0.001). CONCLUSIONS: We found that pre-treatment NLR was an independent prognostic factor for recurrence or metastasis of medulloblastoma after treatment. In combination with NRL and clinical factors, nomogram has a good prediction of PFS in patients with medulloblastoma after radiotherapy. It has the potential to facilitate more precise risk stratification to guide personalized treatment of medulloblastoma.
MEDB-73. Lipid metabolism as a therapeutic vulnerability in BET inhibitor-resistant medulloblastoma
Authors: Leslie Lupien, Adam Boynton, Madison Chacon, Rushil Kumbhani, Gabrielle Gionet, Amy Goodale, David Root, Hasmik Keshishian, Margaret Robinson, Steven Carr, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2022)

Abstract MYC-driven medulloblastomas are a particularly devastating group of pediatric brain tumors that exhibit resistance and continued progression despite standard of care treatments. Our preclinical work identified BET-bromodomain inhibitors as a potentially promising new class of drugs for children with medulloblastoma and other MYC-driven cancers, providing rationale to evaluate these agents in clinical trials. However, treatment with BET inhibitor (BETi) alone is unlikely to be sufficient to cure, with most tumors evolving to acquire resistance to single-agent targeted therapies. We applied an integrative genomics approach to identify genes and pathways mediating BETi response in medulloblastoma. These studies revealed that MYC-driven medulloblastoma cells with acquired resistance to BETi reinstate transcription of essential genes suppressed by drug and exhibit changes in cell state and new vulnerabilities not present in drug-sensitive cells. We now have a growing body of evidence showing that BET inhibition downregulates the expression of key lipid metabolism genes and metabolism-related signaling pathways, and that medulloblastoma cells with adaptive resistance to drug differentially express and exhibit preferential dependency on specific lipid metabolic genes and transcriptional regulators. Our studies explore the possibility of exploiting these metabolic vulnerabilities to overcome BETi resistance and provide a more efficacious upfront therapy.
SURG-10. Pediatric PF-A ependymoma: a case series of cytogenetics and progression-free survival
Authors: Shelly Sharma, Reid Colliander, Michael DeCuypere
Journal: Neuro-Oncology (2022)

Abstract Ultra-high risk PF-A ependymoma, defined as 6q chromosome deletion in the setting of 1q gain, represents a biologically unique entity. These tumors are associated with significantly worse progression-free survival and 6q loss is an independent predictor of overall survival. Here, we present cytogenetics and progression-free survival from all PF-A ependymomas diagnosed at Lurie Children’s Hospital of Chicago over a 10-year period (2011 and 2021). Twelve patients were identified with the diagnosis of PF-A ependymoma (42% males, average age at diagnosis 5.75 years) during the study period. Four patients demonstrated gain of 1q on methylation profiling. Two patients with a gain of 1q also had a deletion of 6q, carrying the ultra high-risk designation. All patients underwent surgical resection and post-operative radiation therapy. Patients who received chemotherapy had a significant increase in overall number of surgical resections (p-value &amp;lt; 0.0001). Patients without 1q gain had an average of 2.1 surgeries, while patients with 1q gain had an average 2.75 surgeries. Patients with 1q gain and 6q deletion had an average of 3.5 surgeries. All patients with 1q gain had recurrence of their tumor, compared to 38% of patients without 1q gain. In this series, progression-free survival for the PF-A without 1q gain, 1q gain, and 1q gain with 6q deletion cohort was 27.9, 18.4, and 19.5 months, respectively. The most common complications were radiation toxicity and cerebellar dysfunction (ataxia, dysmetria, and gait imbalance). Not surprisingly, complications were more common in those patients undergoing a greater number of subsequent resections. All PF-A ependymomas should be evaluated for 1q gain and 6q deletion, which can be reliably ascertained using cytogenetic markers in routine clinical use. In this series, 1q gain was associated with a decrease in progression-free survival. Only 2 patients were designated ultra high-risk based on cytogenetic analysis.